US 20080214675A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0214675 A1 Ley et al. (43) Pub. Date: Sep. 4, 2008 (54) HYDROXYBENZOIC ACIDAMIDES AND THE Publication Classification USE THEREOF FOR MASKING BITTER (51) Int. Cl. TASTE A6II 3/66 (2006.01) C07C 233/73 (2006.01) (75) Inventors: Jakob Ley, Holzminden (DE); A2.3L. I./22 (2006.01) Heinz-Jurgen Bertram, (52) U.S. Cl. .......................... 514/622:564/179; 426/538 Holzminden (DE); Gunter Kindel, (57) ABSTRACT Hoxter (DE); Gerhard Krammer, Holzminden (DE) The use is described of hydroxybenzoic acid amides having formula (I) wherein Correspondence Address: R" to R mutually independently denote hydrogen, hydroxy, ROYLANCE, ABRAMS, BERDO & GOODMAN, methoxy or ethoxy, with the proviso that at least one of the L.L.P. radicals R' to R denotes hydroxy. 1300 19TH STREET, N.W., SUITE 600 and WASHINGTON, DC 20036 (US) R denotes hydrogen, methyl or ethyl and in denotes 1 or 2. (73) Assignee: SYMRISE GMBH & CO. KG, their salts and mixtures thereof, to mask or reduce the Holzminden (DE) unpleasant flavour impression of an unpleasantly tasting Substance and/or to strengthen the Sweet flavour impres (21) Appl. No.: 11/574.277 sion of a Sweet Substance. (22) PCT Filed: Aug. 2, 2005 (I) (86). PCT No.: PCT/EP05/53764 S371 (c)(1), (2), (4) Date: Nov. 13, 2007 (30) Foreign Application Priority Data Aug. 27, 2004 (DE) ...................... 10 2004 O41 496.3 US 2008/0214675 A1 Sep. 4, 2008 HYDROXYBENZOIC ACIDAMIDES AND THE 0010 Neohesperidin dihydrochalcone likewise has a bit USE THEREOF FOR MASKING BITTER terness-reducing effect, but it is primarily a Sweetener (cf. TASTE Manufacturing Chemist 2000, July edition, p. 16-17), which also has an intrusive effect in non-Sweet applications. 0011 Whilst flavour-modifying properties am described 0001. The invention relates to the use of certain hydroxy in U.S. Pat. No. 5,580,545 for some flavones (2-phenyl benzoic acid amides, their salts and mixtures thereof to mask chrom-2-en-4-ones), a bitterness-reducing or Suppressing or reduce unpleasant flavour impressions, particularly bitter, action has not been found. astringent and/or metallic flavour impressions, and/or to (0012 US 2002 177,576 describes the suppression of a strengthen the Sweet flavour impression of a Sweet Substance. bitter taste by nucleotides, for example cytidine-5'-mono Certain of these hydroxybenzoic acid amides are novel. The phosphates (CMP). The highly polar compounds, which can invention also relates to certain preparations which contain an therefore only be used in highly polar solvents, are only of effective content of the hydroxybenzoic acid amides, their very limited use in many fatty foodstuffs, however. In addi salts or mixtures thereof. Finally the invention relates to pro tion, the availability of such substances is extremely limited cesses for producing hydroxybenzoic acid amides for use due to their expensive chemical synthesis. according to the invention. 0002 Foodstuffs or beverages commonly contain various (0013 US 2002 188,019 describes hydroxyflavanones as bitter principles which although on the one hand desirable effective masking agents for bitter tastes, but they are only and characteristic in moderation (e.g. caffeine in tea or coffee, obtainable synthetically with difficulty and are not available quinine in bitter lemon drinks, hop extracts in beer), can on in larger amounts at a reasonable cost. the other hand also severely detract from the value (e.g. fla 0014. The sodium salts sodium chloride, sodium citrate, vonoid glycosides and limonoids in citrus juices, the bitter Sodium acetate and sodium lactate have a bitterness-masking aftertaste of many artificial Sweeteners such as aspartame or effect against many bitter principles (e.g. Nature, 1997, Vol. saccharine, hydrophobic amino acids and/or peptides in 387, p. 563); however, the intake of large amounts of sodium cheese). ions can lead to heart and circulatory diseases, for example. 0003. In order to reduce the natural content of bitter prin Disadvantageously, a significant bitterness-masking effect ciples, a Subsequent treatment is therefore often necessary, by also sets in only with relatively high sodium concentrations extraction for example, as in the decaffeination of tea or (from about 0.1 M), which corresponds for example to a coffee, or by an enzymatic process; e.g. the treatment of generally unacceptably high content of about 0.6 wt.% of orange juice with a glycosides to destroy the bitternaringin or NaCl in the final application (cf R. S. J. Keast, P. A. S. Breslin the use of special peptidases in the ripening of cheese. This and G. K. Beauchamp, Chimie 2001, 55(5), 441-447). treatment places a strain on the product, generates waste (0015 WO 00/21390 describes polyglutamic acid as a bit products and also gives rise to solvent residues and other terness-masking agent; relatively high concentrations of residues (enzymes) in the products, for example. around 1 wt.% are needed in this case. 0004. It is therefore desirable to find substances which can 0016. A lipoprotein consisting of B-lactoglobulin and effectively suppress or at least reduce unpleasant flavour phosphatide acid likewise has a bitterness-masking effect impressions, in particular bitter, astringent and/or metallic (EP-A 635 218). Such polymers are difficult to characterise flavour impressions. and Standardise, however, and have apronounced Soapy after 0005. The suppression of the bitter taste of many pharma taSte. ceutical active ingredients is particularly important, since the 0017. The flavone glycoside neodiosmin 5,7-dihydroxy willingness of patients, particularly patients who are sensitive 2-(4-methoxy-3-hydroxyphenyl)-7-O-neohesperidosyl to bitter principles, such as children, to take the preparation chrom-2-en-4-one likewise has a bitterness-masking effect orally can be significantly increased in this way. Many phar (U.S. Pat. No. 4,154,862), but it is characterised by a disac maceutical active ingredients, for example aspirin, Salicin, charide radical which makes production or isolation and paracetamol, ambroXol or quinine, to name just a very small applicability of the substance much more difficult. selection by way of clarification, have a marked bitter, astrin 0018. The primary object of the present invention was to find Substances which are suitable for masking or reducing gent and/or metallic taste and/or aftertaste. the unpleasant flavour impression of unpleasantly tasting 0006 Although some substances are known which can substances (and which preferably have in particular a bitter partially suppress the bitter taste, many of them are severely ness-masking effect against a large number of bitter prin limited in their application. ciples), do not negatively influence other, not unpleasant, 0007. In U.S. Pat. No. 5,637,618 a bitter taste is reduced using lactisole2O-(4-methoxyphenyl)lactic acid. However, flavours, can be widely used and are easily available. this inhibitor also strongly inhibits the Sweet flavour impres 0019. The stated object is achieved according to the inven sion (cf U.S. Pat. No. 5,045,336), which severely limits its tion through the use of hydroxybenzoic acid amides having applicability. formula (I) 0008 2,4-Dihydroxybenzoic acid potassium salt is (I) described in U.S. Pat. No. 5,643,941 (table column 3, line 18) as a masking agent for the bitter taste of potassium chloride, but it cannot suppress the taste of caffeine, for example. 0009. According to GB 2.380,936 the taste of bitter phar maceuticals is Suppressed with ginger extracts. However, the strong aroma impression and/or the pungency which is com monly to be found in ginger extracts or active ingredients obtained from them is unsuitable for many applications. US 2008/0214675 A1 Sep. 4, 2008 0020 wherein present invention are, for example, spicy, umami, Sweet, salty, 0021) R' to R to mutually independently denote hydro Sour, sharp, cooling, Warming, burning or tingling impres gen, hydroxy, methoxy or ethoxy, with the proviso that at least sions. one of the radicals R to R denotes hydroxy, 0.052 Substances which taste bitter, astringent, sticky, 0022 and dusty, dry, mealy, rancid or metallic are, for example: Xan I0023) R' denotes hydrogen, methyl or ethyl thine alkaloids, Xanthines (caffeine, theobromine, theophyl 0024 and line), alkaloids (quinine, brucine, Strychnine, nicotine), phe 0025 in denotes 1 or 2, nolic glycosides (e.g. sailicin, arbutin), flavonoid glycosides 0026 their salts and mixtures thereofa) to mask or reduce (e.g. hesperidin, naringin), chalcone or chalcone glycosides, the unpleasant flavour impression of an unpleasantly tasting hydrolisable tannins (garlic or elagic acid esters of carbohy Substance and/or b) to strengthen the Sweet flavour impres drates, e.g. pentagalloyl glucose), non-hydrolysable tannins sion of a Sweet-tasting Substance, in other words as a flavour (optionally galloylised catechins or epicatechins and oligo COrrectOr. mers thereof, e.g. proanthocyanidins or procyanidins, thearu 0027. The use of hydroxybenzoic acid amides having the bigin), flavones (e.g. quercetin, taxifolin, myricetin), other above formula (I), wherein polyphenols (y-ory Zanol, caffeic acid or esters thereof), ter 0028 R', R and R mutually independently denote penoid bitter principles (e.g. limonoids Such as limonin or hydrogen or hydroxy, with the proviso that at least one of said nomilin from citrus fruits, lupolones and humolones from radicals denotes hydroxy. hops, iridoids, secoiridoids), absinthin from wormwood, amarogentin from gentian, metallic salts (potassium chloride, 0029 and Sodium sulfate, magnesium Sulfate), pharmaceutical active 0030 R and R* denote hydrogen, ingredients (e.g., fluoroquinolone antibiotics, paracetamol. 0031 and aspirin, B-lactam antibiotics, ambroXol, propyl thiouracil I0032) R' denotes hydrogen, methyl or ethyl PROP. guaifenesin), vitamins (for example vitamin H, 0033 and B-series vitamins such as vitamin B1, B2, B6, B12, niacin, 0034 in denotes 1 or 2, panthotenic acid), denatonium benzoate, Sucralose octaac 0035) is their salts and mixtures thereof, is preferred.